Oleptro

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Clinical Studies Experience

The data described below
reflects exposure in a clinical trial of 406 patients, including 204 exposed to
placebo and 202 exposed to Oleptro. Patients were between 18-80 years of age
and 69.3% and 67.5% of patients had at least one previous episode of depression
in the last 24 months in the placebo and active-treated group, respectively. In
individual patients, doses were flexible and ranged from 150 to 375 mg per day.
The mean daily dose during the 6-week treatment period was 310 mg. The tablets
were administered orally and were given once a day for a total duration of 8
weeks, including the titration period.

Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.

Table 3 presents the summary of
all treatment emergent AEs that occurred at an incidence of ≥ 5% in the
Oleptro group, whether considered by the clinical investigator to be related to
the study drug or not.

Sexual Dysfunction

Adverse events related to
sexual dysfunction (regardless of causality) were reported by 4.9% and 1.5% of
patients treated with Oleptro and placebo, respectively. In the Oleptro group,
ejaculation disorders occurred in 1.5% of patients, decreased libido occurred
in 1.5% of patients, and erectile dysfunction and abnormal orgasm < 1% of
patients.

Vital Signs and Weight

There were no notable changes in vital signs (blood
pressure, respiratory rate, pulse) or weight in either treatment group.

Following is a list of treatment-emergent adverse
reactions with an incidence of ≥ 1% to < 5% (i.e., less common) in
patients treated with Oleptro. This listing is not intended to include
reactions (i) already listed in previous tables or elsewhere in the labeling
(ii) for which the association with treatment is remote, (iii) which were so
general as to be uninformative, and (iv) which were not considered to have
significant clinical implications. Reactions are classified by body-system
using the following definitions: frequent adverse reactions are those occurring
in at least 1/100 patients; Infrequent adverse reactions are those
occurring in less than 1/100 patients.

Monoamine Oxidase Inhibitors (MAOIs)

Serotonergic Drugs

Central Nervous System (CNS) Depressants

Trazodone may enhance the response to alcohol,
barbiturates, and other CNS depressants.

Cytochrome P450 3A4 Inhibitors

In vitro drug metabolism studies suggest that there is a
potential for drug interactions when trazodone is given with cytochrome P450
3A4 (CYP3A4) inhibitors. The effect of short-term administration of ritonavir
(200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of
trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of
trazodone increased by 34%, the AUC increased 2.4-fold, the half-life increased
by 2.2-fold, and the clearance decreased by 52%. Adverse effects including
nausea, hypotension, and syncope were observed when ritonavir and trazodone
were co-administered. It is likely that ketoconazole, indinavir, and other
CYP3A4 inhibitors such as itraconazole may lead to substantial increases in
trazodone plasma concentrations with the potential for adverse effects. If
trazodone is used with a potent CYP3A4 inhibitor, the risk of cardiac
arrhythmia may be increased [see WARNINGS AND PRECAUTIONS] and a lower
dose of trazodone should be considered.

Cytochrome P450 Inducers (e.g., carbamazepine)

Carbamazepine induces CYP3A4. Following co-administration
of carbamazepine 400 mg per day with trazodone 100 mg to 300 mg daily,
carbamazepine reduced plasma concentrations of trazodone and
mchlorophenlypiperazine (an active metabolite) by 76% and 60% respectively,
compared to precarbamazepine values. Patients should be closely monitored to
see if there is a need for an increased dose of trazodone when taking both
drugs.

Digoxin And Phenytoin

Increased serum digoxin or phenytoin levels have been
reported in patients receiving trazodone concurrently with either of these
drugs. Monitor serum levels and adjust dosages as needed.

NSAIDs, Aspirin, Or Other Drugs Affecting Coagulation Or Bleeding

Due to a possible association between serotonin
modulating drugs and gastrointestinal bleeding, patients should be monitored
for and cautioned about the potential risk of bleeding associated with the
concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect
coagulation or bleeding [see WARNINGS AND PRECAUTIONS].

Warfarin

There have been reports of altered (either increased or
decreased) prothrombin times in taking both warfarin and trazodone.

Drug Abuse And Dependence

Controlled Substance

Oleptro is not a controlled substance.

Abuse

Although trazodone hydrochloride has not been
systematically studied in preclinical or clinical studies for its potential for
abuse, no indication of drug-seeking behavior was seen in the clinical studies
with Oleptro. However, it is difficult to predict the extent to which a
CNS-active drug will be misused, diverted, and abused. Consequently, physicians
should carefully evaluate patients for a history of drug abuse and follow such
patients closely, observing them for signs of misuse or abuse of trazodone
hydrochloride (e.g., development of tolerance, incrementation of dose,
drug-seeking behavior).